CLINICAL PHARMACOLOGY in

CRITICAL CARE

LSD

Pharmacology and Therapeutic Dept.,

Clinical-Pharmacology Division,
Faculty Of Medicine,
Gadjah Mada University.
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CRITICAL : pertaining to or of the nature of a crisi

in danger of death;
in sufficient quantity as to constitute a
turning point, as a critical mass or as
critical concentration.

CRITICAL ILLNESSES : often associated with

Circulatory, Respiratory, Hepatic and/or Renal
dysfunction which may alter the pharmacokinetics
and/or pharmacodynamic of drugs.
(Benowitz, N.L.,et al 1997)

Dysfunction of
VITAL ORGANS
POSTOPERATION

ADVERSE DRUG REACTIONS

DRUG INTERACTIONS

CRITICAL ILLNESSES
( ICU / ICCU )

SHOCK
ACUTE INTOXICATIONS
OTHERS
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CRITICAL ILLNESS
often associated :
CIRCULATORY ( Hemodynamics )
RESPIRATORY
HEPATIC and/or RENAL DYSFUNCTION
MULTIORGAN FAILURE
SEVERE INFECTION

may altered :
PHARMACOKINETICS (PK) and/or
PHARMADYNAMICS (PD)
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CRITICAL ILLNESSES
DECISIONS ABOUT ROUTE OF ADMINSTRATION
and DOSES of the medicine;

- physiological status of the patients

- pharmacokinetics and pharmacodynamics characteristics
of the medicine

- how the two interact each other

PHARMACOKINETICS
IN SITE
THE BODY

PHARMACEUTIC

ABSORPTION
DISTRIBUTION
METABOLISM

IN SITE
THE BODY

ELIMINATION /EXCRETION
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The Effects of Critical Illness on

Pathophysiological condition

Drug Pharmacokinetics

Effects on

drug kinetiks

(e

Depressed gut absorptive capacity

Drug absorption altered by enteral
feeding
Increased total body water

Decreased drug absortion (eg: digoxin)

Reduced availability of drug
(eg:phenytoin)
Higher loading dose (eg: gentamicin)
Longer half-life ((eg: vancomycin)

Hypoalbuminaemia

Increased drug-free fraction (eg.

phenytoin)
Delayed drug metabolism,
(eg:benzodiazepine)
Decreased drug clearance (eg.: lidocain)
Decreased drug clearence
(eg :aminoglycoside, digoxin)

Hepatic dysfunction
Decreased hepatic perfusion
Renal dysfunction

PK & PD
In EMERGENCY / CRITICAL CARE :
- DOSAGE
- ROUTES OF DRUG ADMINISTRATION
- DRUGS INTERACTIONarial

If not appropriate :

NEW PROBLEM

PHARMACOKINETIC CONSEQUENCES OF CIRCULATORY FAILURE

arythmias

tamponade

Valvular dysfunc.

Myocard.failr.

haemorrhage

hypertension

CIRCULATORY FAILURE
Inadequate cardiac output
Auto regulation, redistribution of blood flow.

Slow distribution
of drug to tissues

Greater %age of CO
to well perfused
organs

Decreased blood
flow to kidney

Decreased GFR,
increased tubular reabsorp.,
decreased tubular secretion

Higher initial drug

concentration in
blood
Higher initial drug
concentration in well
perfused tissues
(brain, heart)

Shunting of renal
blood from cortical
to juxtamedullary
nephron

Dcreased drug
excretion

Decreased
clearance of
highly extracted
drugs

Decreasedt
blood flow
to liver

Impaired
hepatocellular
function

Decreased
clearance of poorly
extracted
drugs
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1.
2.
3.
4.
5.
6.
7.
8.
9.

CIRCULATORY FILURE
ALTERED FLUID BALANCE
HEPATIC FAILURE
RENAL FAILURE
ACUTE PULMONARY INSUFFICIENCY
INFECTIONS / FEVER
BURNS / MULTIPLE ORGAN FAILURE
ACID-BASED DISTURBANCES
DRUG INTERACTIONS (in critical ill patients)

Pharmcokinetics :

absorption;
distribution;
metabolism;
excretion.

Pharmacodynmics :

responses of tissues/organs
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CRITICAL CARE MANAGEMENT

(general principles)
1.Preservation of Cardiovascular, Respiratory and
Metabolic function.
- Physiological monitoring : vital signs, CNS, ECG, intra-arterial
catheters (unstable BP), blood gas analysis, electrolytes,
EEG, etc.
- Preservation of Cardiovascular Function :
fluid & electrolytes, myocardium ( by streptokinase or t-PA,
tissue-type plasminogen activator in acute attack <6 hours ),
BP control by anti hypertensive,etc.
- Preservation of Respiratory Function :
mayor critical ill e.g. pulmonary oedema (acute respiratory
distress syndrom / ARDS) and pneumonia adequate
oxygenation, management of infection (pneumonia / sepsis).
- Pay attention metabolic factors
monitoring hepatic and renal function, control quality of food,
nitrogen balance, etc
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2. Fluid therapy.
Objective : to replete intravascular volume.
Condition : haemorrhage, vomiting, diarrhoe, excessive diuresis,
inadequate fluid intake and redistribution of
fluid out of the vascular space intravascular volume
depletion hypotension inadequate organ perfusion.
Target : clinical sign of inadequate perfusion no longer evident or
CVP (central venous pressure) 12 15 mmH2O especially
brain.
Until BP reached adequate organ perfusion.
Fluid replacement : isotonic solution (normal saline, R.Lactate,etc),
colloid ( albumin, dextran, plasma expander ) or blood
component.

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3. Cerebral proctection.

Metabolic demands of the brain : maintain adequate blood flow,

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adequate oxygen, and glucose.
Controlled the fever, seizure, etc.

4. Anti-infective Therapy.

Critical ill patients have a high risk of infection because impaired

host defence and multiple invasive procedures ( oxygen canule,
endotracheal tube, nasogastric tube, urinary catheter, iv catheter
etc. )

5. Prophylaxis

Gastric Stress Erosions and Ulcers gastrointestinal

bleeding.
Prophylactic : H2 blocker ) cimetidine, ranitidin, sucralfate, etc.

6. Pulmonary embolism

: cause by prolonged immobility, tissue injury

and/or activation of coagulation. DVT present 58% in majot and large
trauma (hip & knee replacement)
If thrombotic risk very high : prophylaxis use LMWH (low molecular
weight heparin) like enoxaparin.
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7. AVOIDING ;
DRUG-INDUCED COMPLICATION.
- multiple pharmacotherapy / polypharmacy interaction.
- to minimise :
a. consider the effects of the presence of organ dysfunction
on pharmacokinetics and adjust initial drug doses;
b. Set specific end-point for therapy (where possible);
c. monitor drug concentration if possible;
d. monitor patients for early evidence or toxicity;
e. Review medication record in total on a regular basis to detect
possible adverse drug interactions.

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SPECIFIC CRITICAL CARE CONDITIONS

1.SHOCK
2.ANAPHYLAXIS
3.ACUTE RESPIRATORY FAILURE
4.ARDS (acute respiratory distress syndromes)
5.BRAIN INJURY
6.DISORDERS OF BLEEDINGS

(HAEMORRHAGY;HEMATEMESIS; MELENA;HEMOPTOE)

7. HEART PROBLEMS ( AMI, etc)

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ANAPHYLAXIS.
The leading cause : drugs; foods; insect stings; extracts
of allergens increased vascular permeability
loss of plasma depletion of intravascular
volume & tissue oedema.
Treatment : - antagonising the effects of chemical mediators;
- preventing further release of mediator;
- minimising exposure to the inciting agent.
Pharmacotherapy : - adrenaline
- 2-adrenoceptor agonist (salbutamol,
orciprenalin)
- antihistamines
- corticosteroids
- vasopressors ( noradrenaline, methoxamine)
methoxamine

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ACUTE RESPIRATORY FAILURE.

May as complication of:

chronic obstructive lung disease
ARDS
severe pulmonary infection
diaphragmatic muscular weakness / paralysis
massive obesity
CNS dysfunction (due brain injury; drug over dose)

Clinical : somnolence; confusion; disorientation / coma; depressed

respiration; and cyanosis.
Laboratory : arterial bllod gas analysis : hypoxaemia; CO retention.
Therapy : -

low flow oxygen by nasal canule or mask;

higher oxygen concentration via ETT;
bronchodilators (inhaled 2-agonist);
corticosteroids (asthma; COPD);
specific therapy to the cause.
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ACUTE RESPIRATORY DISTRESS SYNDROME / ARDS

( = non-cardiogenic pulmonary oedema )
Cause ARDS : sepsis; trauma; shock; burns; aspiration pneumonia;
drug overdose; inhalation of toxic substance; oxygen
toxicity and fat emboli.
Pulmonary oedema : injury to pulmonary capillary endothelial cells
and to the epithelial cells that line the alveolus
and provide the tightest barrier to fluid and
protein movement fluid leaks into alveoli.
Treatment of ARDS : - oxygenation by mechanical ventilation PO2
70 80 mmHg.
- PEEP (positive end-expiratory pressure) or
CPAP (continous positive airway pressure).
- haemodynamic monitoring by fluid therapy
- drug : no specific treatment, depend the
condition. Usually diuretic or vasodilators,
vasopressor (dopamine).
- specific treatment for complicating illness. 18

BRAIN INJURY
-Head trauma
-Cerebrovascular disease
-Infection
-Anoxia (carbon monoxide poisoning)
-Global ischaemia (severe shock, post cardiac arrest)

Clinical sign : cerebral edema

increased intracranial pressure > 15 mmHg
(by space-occupying lesion: tumor,haematom
abscess)
Treatment : cerebral edema
- osmotic agent (mannitol and glycerol)
- corticosteroid (for suppressing inflammation and
decreasing capillary permeability)
- barbiturates (reduction cerebral metabolic
activity) common use in Reyes syndrome.

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INTRACRANIAL HYPERTENSION (1)

MANAGEMENT:
- monitoring: neurological status
intracranial pressure
intra-arterial pressure
(intracranial pressure
< 40 50 mmHg poor prognosis).
- maintain & normalizing metabolic function
(oxygenation and blood glucose concentration).
- adequate venous drainage (position 30 degree
head-up tilt).

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INTRACRANIAL HYPERTENSION

(2)

surgical decompression

hyperventilation but PaCO2 not reduce below 20 mmHg

( target value : 25 mmHg )

- anti-edema therapy :
20 % manitol or 10 % glycerol
frusemid ( a diuretic )
high dose corticosteroid
( suppressing inflammation )

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COMPLICATION OF
DRUG INTOXICATION

1.
2.
3.
4.
5.
6.
7.
8.

DRUG-INDUCED
DRUG-INDUCED
DRUG-INDUCED
DRUG-INDUCED
DRUG-INDUCED
DRUG-INDUCED
DRUG-INDUCED
DRUG-INDUCED

COMA
AGITATED DELIRIUM
SEIZURES
HYPERTHERMIA
HYPERTENSION
ASPIRATION PNEUMONIA
PULMONARY OEDEMA
ARRHYTHMIAS

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MONITORING & EVALUATE;

-> THE FUNCTION OF VITAL ORGANS :
brain, heart, lungs, kidney, GIT, etc
-> DO IT PERIODICALLY :
by test function/physiological,
laboratory, electromedic, radiologic
-> In INTENSIVE CARE UNIT (ICU; ICCU)

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Thanks for your attention

and

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